Handbook of Clinical Neurology, Vol. 120 (3rd series) Neurologic Aspects of Systemic Disease Part II Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved
Chapter 75
Hemolytic uremic syndrome 1
KATHLEEN WEBSTER1* AND EUGENE SCHNITZLER2 Department of Pediatrics, Loyola University Medical Center, Maywood, IL, USA
2
Department of Neurology, Loyola University Medical Center, Maywood, IL, USA
INTRODUCTION The terms “microangiopathic hemolytic anemia” and “thrombotic microangiopathy” have been used to describe disorders consisting of endothelial cell damage, thrombosis, and resulting thrombocytopenia and red cell destruction. Two important causes of these findings are hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP). Both disorders can lead to widespread organ damage and predominantly affect the brain and kidney. In TTP, renal disease is less common and neurologic involvement is more pronounced. Although TTP is more commonly reported in adults and HUS in children, there have been reported cases of each disorder occurring outside of the typical age ranges and both should be considered in the appropriate clinical setting (Moake, 2002).
DEFINITION HUS was first described by Gasser and colleagues in 1955. It is defined by the triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure (Eriksson et al., 2001; Scheiring et al., 2008; Johnson and Taylor, 2009; Michael et al., 2009). Typical (D þ) HUS follows within 2 weeks of an acute diarrheal illness. Atypical (or D ) HUS has also been reported and accounts for 10–20% of reported cases. Potential etiologies of atypical HUS include complement deficiency, inborn errors of metabolism, medications, infectious agents, and autoimmune disease processes (Table 75.1). The distinction between these two types can be important with regards to etiology, pathogenesis, long-term course, and treatment. Atypical HUS (aHUS) is associated with an increased risk of seizures and other
neurologic complications (Johnson and Taylor, 2009; Michael et al., 2009; Scheiring et al., 2010).
EPIDEMIOLOGYAND ETIOLOGY Although HUS is most commonly known as a leading cause of acute renal failure in children (Cerda et al., 2008), other organ systems have also been reported to be affected, particularly the central nervous system (CNS) (Eriksson et al., 2001; Banerjee, 2009; Scheiring et al., 2010). It is reported that up to half of children with HUS will have CNS involvement, most commonly in the form of seizures, altered mental status, or coma. HUS is estimated to occur with a frequency of 0.3–3.3 per 100 000 children worldwide, although it is noted that the incidence has been increasing in the past decade (Eriksson et al., 2001; Pomajzl et al., 2009). The most commonly affected age groups are children less than 5 years old, accounting for 50–70% of cases, and adolescents. Infants have rarely been reported to be affected. Up to 40% of children may require critical care support. Mortality from HUS is 2– 7%, with higher risk seen in females, children under 5 years of age, the elderly, and patients with atypical or recurrent HUS (Gould et al., 2009; Rust and Worrel, 2009). In both typical HUS and aHUS, early presentation of CNS symptoms is associated with a less favorable outcome (Rust and Worrel, 2009; Scheiring et al., 2010).
Typical hemolytic uremic syndrome The typical presentation of HUS occurs following a diarrheal prodrome. Diarrhea is infectious, usually due to Shiga toxin-producing Escherichia coli (STEC) (Ruggenenti et al., 2001; Michael et al., 2009). Although the 0157:H7 subtype of E. coli is the most commonly identified in the US, other subtypes have been found (Centers for Disease Control, 2009; Melmann et al., 2009). Of
*Correspondence to: Kathleen Webster, M.D., Loyola University Medical Center, 2160 S 1st Avenue, Maywood, IL 60153, USA. Tel: þ1-708-327-9137, Fax: þ1-708-216-5602, E-mail: [email protected]
1114
K. WEBSTER AND E. SCHNITZLER
Table 75.1 Etiologies of atypical hemolytic uremic syndrome Infectious
Noninfectious
STEC infection Diarrheal
Complement deficiency Cobalamin metabolism deficiency Malignancy Transplant SLE Antiphospholipid syndrome Pregnancy HELLP syndrome Medication-induced Quinine Oral contraceptives Immunosuppressants Tacrolimus Ciclosporin Mycophenolate
Urinary Other diarrheal infections Shigella Citrobacter Yersinia Clostridium difficile Giardia Viral infections HIV H1N1 influenza A CMV EBV Other infections Pertussis Malaria Pneumococcal
STEC, Shiga toxin-producing Escherichia coli; HIV, human immunodeficiency virus; CMV, cytomegalovirus; EBV, Epstein–Barr virus; SLE, systemic lupus erythematosus; HELLP, hypertension, elevated liver enzymes, low platelets.
note, although E. coli 0157:H7 is well known as the cause of HUS, only 8% of persons with diarrheal illness due to this organism go on to develop HUS. Other infectious causes of diarrhea have been identified in afflicted patients, including Shigella, Citrobacter, Yersinia, Clostridium difficile and Giardia (Besbas et al., 2006; Pomajzl et al., 2009). STEC associated HUS accounts for up to 90% of cases and follows a seasonal pattern with higher incidence in summer and fall. Food-borne outbreaks have been reported and may be associated with raw ground beef, unpasteurized juice or milk, fresh produce such as lettuce, spinach, and alfalfa sprouts, and contaminated water (Razzaq, 2006; Rivero et al., 2010). The bacteria may be easily spread, and infection may be acquired from contact with animals and their environment, or other infected persons. In cases of multiple family members with symptoms it is important to distinguish concurrent HUS with diarrheal symptoms from asynchronous events, which may be related to genetic causes or complement deficiencies (Centers for Disease Control, 2009; Pomajzl et al., 2009).
Atypical hemolytic uremic syndrome Atypical HUS (aHUS) is being described in a growing body of literature and is more commonly associated with
neurologic sequelae. In addition to diarrheal infections, HUS may be triggered by STEC infection of the urinary tract. Viral infections may also be associated with HUS. Reported cases have involved human immunodeficiency virus (HIV), novel H1N1 influenza A, cytomegalovirus (CMV), Epstein–Barr virus (EBV), and others (Ariceta et al., 2009; Banerjee, 2009; Printza et al., 2011; C¸altik et al., 2011). There are also several case reports of infants with HUS related to pertussis (Chaturvedi et al., 2010). Sharma et al. (1993) reported HUS following malaria. Another notable infectious cause is bacteremia, meningitis, or empyema due to Streptococcus pneumoniae. This particularly virulent form of HUS mainly affects children under 2 years of age and is associated with a much higher mortality (Brandt et al., 2002; Barit and Sakarcan, 2005; Besbas et al., 2006; Lei et al., 2010; Scheiring et al., 2010). Atypical HUS is most commonly related to noninfectious causes. Over 50% of cases are attributed to congenital or acquired complement deficiency, notably disorders of factor H, factor I, factor B, and membrane cofactor protein (MCP) (Quintrec et al., 2010). Abnormal processing of cobalamin (vitamin B12) leading to severe deficiency is an inborn error of metabolism and well described as an etiology of a particularly severe form of HUS with a high rate of neurologic symptoms (Sharma et al., 2007). Other reported associations with atypical HUS are malignancies, chemotherapy, systemic lupus erythematosis (SLE), antiphospholipid syndrome, pregnancy, and HELLP syndrome, and with medications such as quinine or oral contraceptives (Besbas et al., 2006; Michael et al., 2009; Scheiring et al., 2010). Patients who have had solid organ or bone marrow transplant also seem to be more susceptible to development of HUS. It is unclear whether this is due to the transplant state itself or due to immunosuppressive medications, such as tacrolimus, ciclosporin, and mycophenolate (Ariceta et al., 2009; Banerjee, 2009). In many of the atypical cases of HUS, it has been proposed that both a genetic predisposition and an environmental trigger are required to produce disease (Johnson and Taylor, 2008).
Thrombotic thrombocytopenic purpura The presentation of HUS is closely related to thrombotic thrombocytopenic purpura (TTP). Like HUS, TTP is associated with microangiopathic hemolytic anemia and thrombocytopenia. The initial description of TTP by Moschowitz in 1925 reported a “pentad” of these two findings in addition to fever, neurologic impairment, and renal dysfunction. As in HUS, platelet aggregation occurs, although the etiology in TTP is deficiency of a protease known as ADAMTS13. This deficiency
HEMOLYTIC UREMIC SYNDROME may be congenital, known as Upshaw–Schulman disease, with presentation occurring early in childhood, even in infancy (Schneppenheim et al., 2004; Lowe and Werner, 2005). Acquired deficiency may be related to autoantibodies against ADAMTS13 and present later in life, triggered by medications, collagen vascular disease, or infection. Untreated, the mortality of TTP is over 90%, although with plasma therapy, the incidence of mortality drops to 10–20%. In the current literature, there is disagreement as to whether TTP is a distinct syndrome from HUS, or whether these two disorders represent a spectrum of disease. HUS is classically thought of as a renal disease with systemic effects, while TTP is considered as a systemic disease with effects on the central nervous system and kidney (Desch and Motto, 2007). Often the two disorders are difficult to distinguish based on clinical presentation alone and further testing of complement and genetic factors is required to make a definitive diagnosis. Many of the same medications and diseases can trigger TTP and atypical HUS (Nolasco et al., 2005; Desch and Motto, 2007). It remains to be seen whether these two disorders will be found to be more similar or more distinct as the pathophysiology continues to be explored.
PATHOPHYSIOLOGY As described above, a wide range of etiologies of typical and atypical HUS and TTP are reported. Although each of these results in a common clinical picture, the pathophysiology of each is distinct.
Typical hemolytic uremic syndrome In STEC-associated HUS, the infecting organism enters the gastrointestinal tract and binds to and causes inflammation of the intestinal epithelium (Pomajzl et al., 2009). The bacteria produce a toxin, called Shiga toxin (Stx) or verotoxin. The toxin enters the bloodstream, bound to a carrier such as monocytes, neutrophils, or platelets. The toxin binds to the globotriaosyl ceramide (Gb3) receptor. The toxin results in red cell lysis and damage to vascular endothelium. This in turn leads to a cascade of microthrombosis, platelet activation, and thrombotic injury to the vasculature (Lowe and Werner, 2005; Karpman et al., 2010; Scheiring et al., 2010).
Atypical hemolytic uremic syndrome Atypical HUS may be caused by a variety of etiologies, each with a different trigger resulting in the final common pathway of inflammatory cascade causing renal endothelial and vascular injury and resultant thrombotic microangiopathy. Up to 50% of patients may have chromosome 1 mutations or autoantibody production leading
1115
to deficiency and dysregulation of the complement cascade (Loirat et al., 2008; Banerjee, 2009). Another mutation on chromosome 1 may lead to deficient processing of cobalamin (vitamin B12). This leads to a defect in the processing of cobalamin, with associated homocystinuria and methylmalonic academia (Sharma et al., 2007; Banerjee, 2009; Bouts et al., 2010; Martinelli et al., 2011). This form of aHUS usually presents in infancy and is associated with significant neurologic manifestations including hypotonia, lethargy, feeding difficulties and failure to thrive (Ariceta et al., 2009). Finally, pneumococcal infection may lead to production of neuraminidase, which exposes a protein known as Thomsen-Friedenreich antigen (TF-Ag) on renal endothelial cells, and causing immune activation (Banerjee, 2009; Bouts et al., 2010).
CLINICAL MANIFESTATIONS In typical HUS, the history may include exposure to contaminated food. Symptoms generally develop 1–8 days following ingestion of the offending agent. Clinically the child usually presents with bloody diarrhea and cramping abdominal pain. Physical examination may show petechiae and/or mucosal bleeding. Diagnostic criteria include anemia, thrombocytopenia, and elevated creatinine. An “incomplete” HUS has been described in children who present with bloody diarrhea, anemia, and thrombocytopenia but have mild or absent elevation of creatinine and do not go on to develop overt renal failure (Lowe and Werner, 2005; Besbas et al., 2006; George, 2009; Scheiring et al., 2010). The differential diagnosis includes sepsis and disseminated intravascular coagulation (DIC), SLE, and TTP. Of note, in both HUS and TTP, other markers of coagulation including PT and aPTT are normal, thus distinguishing these from DIC. Since the anemia is due to hemolysis, the peripheral blood smear will often reveal schistocytes and helmet cells (Lowe and Werner, 2005). Most HUS will have a negative direct Coombs test, with the notable exception of that following S. pneumoniae infection, in which up to 90% may be positive (Banerjee, 2009; Scheiring et al., 2010).
NEUROLOGIC FINDINGS AND SEQUELAE CNS involvement occurs in 20–50% of patients with hemolytic uremic syndrome and is usually seen within the first week of illness (Bale et al., 1980). CNS symptoms may be mild with many patients demonstrating only irritability and lethargy. More severe CNS presentation may be manifested by seizures, stupor, coma, and hemiparesis. Aphasia, ataxia, chorea, dystonia, and visual disturbances may also occur (Hahn et al., 1989). Cerebral edema with headache, vomiting, papilledema,
1116 K. WEBSTER AND E. SCHNITZLER sixth nerve weakness, and altered mental status is comand hearing loss. Dialysis is frequently used as a treatmonly observed. HUS presenting with early CNS signs ment modality for HUS and is associated with improved and symptoms is associated with higher rates of mortalsurvival and prevention of encephalopathy (Stewart and ity as well as neurologic and non-neurologic sequelae Tina, 1993); however, dialysis itself may cause neuro(Upadhyahya et al., 1980). logic abnormalities. Headache is commonly observed The etiology of CNS pathophysiology in HUS is mulduring dialysis in adults, adolescents, and older children. tifactorial but underlying mechanisms closely parallel Headaches may be migraine variants or secondary to those attributed to acute renal failure (ARF). ARF has water intoxication or hypertension. Headache is also a been known to be associated with altered mental status component of the dialysis disequilibrium syndrome for more than a century. Although a significant degree which also includes mental status changes, fatigue, of renal failure can be tolerated without neurologic and muscle cramps. In more severe cases of dialysis diseffects, rapid deterioration of kidney function such as equilibrium syndrome, seizures and coma may develop. occurs in HUS is more likely to result in precipitous alterDialysis disequilibrium syndrome tends to occur early in ation of neurologic status (Eriksson et al., 2001). the course of dialysis and as a complication of rapid dialThe neurologic deterioration seen in HUS with ARF ysis. The underlying pathophysiology is incompletely relates to uremia, hypertension, and altered fluid and understood but seems to be secondary to cerebral edema electrolyte metabolism. Water intoxication is seen early produced by osmotic gradients of urea and other osmotin the course of ARF and is accompanied by hyponatreically active compounds (Rust and Chun, 1999). mia. Early clinical signs of water intoxication include Although hypertension, dialysis equilibrium synheadache and altered mental status which can progress drome, and the metabolic changes of ARF account for rapidly to seizures and coma. Uremia in HUS is primarily a significant proportion of the CNS pathophysiology due to glomerular injury resulting in failure of excretion seen in HUS, other factors appear to be involved. of toxic catabolites of protein. This is accompanied by Dhuna et al. (1992) reported a series of 11 children with acidosis with an increased ion gap, bicarbonate wasting, HUS and seizures. Generalized seizures occurred in four and elevated serum potassium levels. Early uremic patients and partial seizures in seven patients. The chilencephalopathy is characterized by subtle changes in dren with generalized seizures had diffuse slowing on mental status including irritability, inattentiveness, conEEG and normal CT scans of the brain. All four children fusion, memory lapses, lack of interest, fatigue, speech had a normal outcome. However, in the patients with dyspraxia, and mild cognitive impairment. These symppartial seizures, there was diffuse slowing, but focal toms may be followed by movement disorders, particuslowing, focal spikes, asynchronous slowing, and burst larly tremor, tetany, and asterixis. Primitive reflexes suppression patterns were also noted. Six of the seven such as snouting and rooting sometimes occur. Hemiparpatients with focal seizures had clinical findings of hemiesis and transient loss of vision and hearing have also paresis. CT scans in these six patients demonstrated been noted. Uremia may also produce generalized weakstrokes primarily in the basal ganglia and thalamus. ness secondary to neuropathy (Rust and Chun, 1999). All six patients recovered with residual hemiparesis. Seizures occur in up to 40% of children with uremia Thus, partial seizures in HUS were correlated with focal secondary to HUS. These are usually generalized but EEG changes and structural pathology. Strokes secondmay also be focal or myoclonic. Hypertension due to ary to infarctions and microinfarctions seemed to ARF also typically results in an encephalopathy characaccount for these structural findings. terized by generalized seizures as well as headache and Sheth and associates (1986) reviewed 44 children with visual changes. Focal findings including aphasia, hemiHUS seen between 1972 and 1984. Fifteen patients had paresis and particularly sixth nerve palsies have been neurologic complications including 12 who had seizures. described. Occipital blindness is common with hypertenStatistically significant correlations were noted between sive encephalopathy of various etiologies including CNS involvement and metabolic abnormalities including ARF. This is referred to as “reversible posterior leukoenhypocalcemia, hypocapnia, and elevated serum creaticephalopathy” or “occipital-parietal encephalopathy.” nine levels. CSF protein was elevated in four patients, Correlating magnetic resonance imaging (MRI) and but there were none with CSF pleocytosis or decreased computed tomography (CT) findings of white matter CSF glucose. Only six patients with CNS involvement edema without infarction have been noted to accompany recovered completely. Three patients died and six had the clinical loss of vision (Sebire et al., 1995; Hinchey neurologic and/or renal residuals or hypertension. Postet al., 1996). mortem examination of one patient who died showed Early dialysis is effective in prevention and reduction probable cerebral edema but no findings of any vascular of symptoms of uremic encephalopathy as well as microthrombi. Eriksson et al. (2001) summarized EEG improving outcomes in cases of uremic neuropathy data in 22 patients with HUS. They noted that patients
HEMOLYTIC UREMIC SYNDROME 1117 with periodic activity as well as focal and multifocal epineurologic involvement does not necessarily imply poor leptogenic activity had higher rates of mortality, epiprognosis and that basal ganglia involvement in particulepsy, and neurologic sequelae. In particular, focal lar is often associated with full recovery or only mild occipital and temporal slowing and epileptiform disresiduals. Favorable outcome following CNS involvecharges were correlated with residuals of vision impairment even with thrombotic strokes has also been ments and complex partial seizures. The majority of reported by others (Steinberg et al., 1986; Ogura et al., patients with only generalized slowing on EEG recovered 1998; Nakahata et al., 2001). without neurologic complications. Predilection for basal ganglia involvement in HUS Rooney et al. (1971) reported a series of postmortem was corroborated by Steinborn et al. (2004). They neuropathologic findings in HUS patients and did not reviewed MRI and CT scans in 10 patients with HUS describe any unique markers for the disorder. They who had significant CNS involvement. Some 60% had noted cerebral edema and hypoxic changes. In contrast imaging abnormalities in the basal ganglia. AbnormaliUpadhyaya and associates (1980) reviewed 15 patients ties were also seen in the brainstem, cerebellum, and with HUS, three of whom died. Microthrombi were thalami. These signal changes were suggestive of microfound in the kidneys and lungs in all three patients but infarctions. The authors concluded that the basal ganglia also in the brain in two out of the three deceased patients. are commonly affected in HUS and a direct toxic effect The authors speculated that nonrenal multiple organ of verotoxin was again postulated. Furthermore the microthrombi formation seemed to correlate with a imaging findings were often reversible and did not more fulminant course in patients with HUS. necessarily imply an adverse outcome. The presence In a 1980 series, by Bale et al., of 60 patients with HUS, of hemorrhage in a lesion seemed to correlate with subhalf had encephalopathy and/or seizures. CNS involvesequent gliotic or cystic MRI findings as well as residual ment was correlated with azotemia, hyponatremia, and neurologic dysfunction. Two of the MRIs in this series the need for dialysis. Coma on admission and elevated of patients also included diffusion-weighted imaging CSF protein were associated with subsequent mortality (DWI). A case with DWI demonstrating basal ganglia and neurologic morbidity. Only one patient died and lesions was also described by Toldo and associates was autopsied. No microthrombi were seen in the brain. (2009). DWI may be more sensitive in determining neuOnly edema and anoxic changes were noted. rologic prognosis in that reduced apparent diffusion Neuroimaging with CT and MRI has proven to be coefficient (ADC) may correlate with irreversible valuable in the diagnosis, treatment, and prognosis of lesions. A summary of the clinical EEG and neuroimagHUS. Hahn and associates (1989) reported 78 children ing findings in HUS is found in Table 75.2. with HUS; 16 had neurologic complications. CT scans The neuropsychological prognosis of children survivshowed cerebral edema in four patients, large vessel ing HUS has generally been favorable even in patients infarctions in four patients, and multiple hemorrhages who had coma and seizures. Qamar and associates in one patient. At autopsy of three patients, cerebral (1996) reviewed the long-term neurologic and psychoeedema was found but no microthrombi or large vessel ducational outcomes of seven children who had experithrombi were noted. In one patient there was a large enced at least one seizure during their acute presentation hemorrhagic infarction. with HUS. Three children had normal neurologic examIn 1987, DiMario et al. first reported a lacunar infarcinations but four demonstrated mild neurologic abnortion in the basal ganglia as a complication of HUS in a 5malities such as clumsiness, fine motor deficits, year-old girl. Following initial presentation with mild hyperactivity, and distractibility. However, in-depth psyencephalopathy, she developed a left hemiparesis. chometric studies revealed normal IQ scores and behavMRI demonstrated increased T1- and T2-weighted ioral indices in all seven children. In a Canadian images in the consistent with a subacute hemorrhagic multicenter study of 91 case control pairs, Schlieper infarction in the right caudate and lentiform nuclei. and associates (1999) found no significant impact on Barnett and associates (1995) presented two additional cognitive skills, learning, or academic achievement meacases with HUS complicated by coma and dystonic possured at least 6 months after the acute episode of HUS. A turing. MRI and CT scans showed signal changes in the subtle but significant effect of severity of HUS as meabasal ganglia bilaterally. The authors reviewed the litersured by serum creatinine was correlated with lower ature on eight other patients with basal ganglia involvescores on subtests of verbal abilities. However, the inciment. They postulated possible etiologies including dence of attention deficit disorder was no higher in surmicrothrombi secondary to endothelial cell damage vivors of HUS than in age-matched controls. and/or direct effects of the enteric verotoxin. Since the Cimolai and associates (1992) reviewed the risk facmajority of patients recovered, the authors hypothesized tors associated with CNS involvement in HUS in 91 a reversible process. Furthermore they noted that patients. They concluded that younger age and prior
1118
K. WEBSTER AND E. SCHNITZLER
Table 75.2 Clinical EEG and neuroimaging findings in hemolytic uremic syndrome with central nervous system involvement Clinical findings Mild CNS involvement
Prognosis: favorable for recovery
Irritability, lethargy, headache, altered mental status
EEG
CT, MRI
Normal, mild diffuse slowing
Normal, mild cerebral edema
Clinical findings Severe CNS involvement
Prognosis: variable, increased mortality and neurological sequelae
Seizures, stupor, coma, hemiparesis, aphasia, movement disorders, papilledema, visual disturbances, sixth nerve palsy
EEG
CT, MRI
Diffuse slowing, focal slowing, asynchronous slowing, focal spikes burst suppression
Reversible posterior leukoencephalopathy. Infarction and micro-infarctions, primarily in the basal ganglia and thalamus
treatment with gastrointestinal antimotility drugs led to a higher risk of development of HUS in patients infected with Escherichia coli 0157:H7. Using multivariate analysis significant CNS risk factors included female gender, prolonged use of an antimotility drug, and increased hemoglobin levels. Conversely, prior treatment with blood products was associated with a lower risk of neurologic findings. The increased risk factor of female gender applied only to presentation with encephalopathy but not to seizures. The antimotility drugs included opium, codeine, loperamide, diphenoxylate, and anticholinergics. The association of gastrointestinal antimotility agents suggests several possible etiologic mechanisms including more prolonged gastrointestinal absorption of verotoxin. In addition these agents may have direct CNS toxicity which might be further enhanced by impaired renal excretion. It should also be noted that these agents are no longer routinely prescribed by pediatricians for the treatment of diarrhea in infants and young children (Bell et al., 1997).
DIAGNOSIS Diagnosis of typical HUS is usually made clinically based on history and laboratory findings (Table 75.3) (Levandosky et al., 2008; Johnson and Taylor, 2009). All children with diarrheal HUS should have culture of the
stool performed. E. coli 0157:H7 is identified by growth on selective agar within 24 hours. Further testing with PCR or EIA may be done. Although these tests are rapid, they are best performed on colonies already isolated on a culture plate, or from enriched broth that has been incubated. Therefore the earliest confirmed diagnosis still requires 24–36 hours to complete (Centers for Disease Control, 2009). In addition to stool, urine culture for STEC has been reported to be positive, even in the absence of diarrhea. Abdominal ultrasound may be useful in diagnosis during the prodromal phase by identifying thickening of large bowel wall and echogenicity of renal parenchyma (Glatstein et al., 2010). In atypical HUS, a risk factor or deficiency can be identified in approximately 60% of cases (Ariceta et al., 2009). Bacterial culture may help to identify pneumococcal infection as a trigger. For all other causes, serum testing may be of use. Due to the wide range of testing and expense and length of time to diagnosis, a prioritized and stepwise approach to diagnosis is recommended (Table 75.4); however, if therapy with plasma infusion or pheresis is being considered, it is necessary to obtain serum samples prior to initiation of therapy (Banerjee, 2009) or wait a minimum of 2 weeks following plasma infusion (Kavanagh et al., 2007). The most common etiology of atypical HUS is complement deficiency (Besbas et al., 2006; Ariceta et al., 2009). Serum
HEMOLYTIC UREMIC SYNDROME
1119
Table 75.3 Diagnosis of typical hemolytic uremic syndrome History
Laboratory study
Diarrhea within past 2 weeks Age > 6 months Endemic area Exposure to contaminated food Abrupt onset Single episode Concurrent affected contact
Classic features Chemistry panel CBC Hemolytic studies Peripheral smear
Etiologic studies Stool culture Selective agar for E. coli 0157 Serotyping of isolates PCR for Stx1, Stx2
LDH Haptoglobin Coagulation studies PT, PTT Fibrinogen D-dimer Red cell production Reticulocyte count
Findings
Elevated BUN Elevated creatinine Anemia Thrombocytopenia Schistocytes Helmet cells Burr cells Elevated Decreased
Normal Normal Elevated Elevated
PCR, polymerase chain reaction; Stx, Shiga toxin; CBC, complete blood count; LDH, lactate dehydrogenase; PT, prothrombin time; PTT, partial thromboplastin time; BUN, blood urea nitrogen.
Table 75.4 Approach to diagnostic and etiologic work-up in atypical hemolytic uremic syndrome Clinical factor
Possible etiology
Suggested testing
Meningitis, pneumonia
Pneumococcal infection
Age < 6 months, failure to thrive, neurologic symptoms Other atypical HUS
Deficient cobalamin metabolism
Culture of affected site Direct Coombs test Urine and serum amino acids C3, C4 levels Factor H, B, I levels MCP expression ADAMTS13 activity
Neurologic symptoms, family history, insidious onset
Complement deficiency
TTP
HUS, hemolytic uremic syndrome; TTP, thrombotic thrombocytopenic purpura; MCP, membrane cofactor protein; ADAMTS13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13.
assays for levels of C3 along with complement factors H, I and B and MCP should be obtained. If a low level is found, genetic testing or autoantibody assays may also be considered (Kavanagh et al., 2007). In children with coexisting failure to thrive and prominent neurologic symptoms, assessment of urine and serum amino acids may reveal congenital cobalamin deficiency (Ariceta et al., 2009; Banerjee, 2009). For patients in whom TTP is suspected, activity of the enzyme ADAMTS13 may be analyzed. Activity < 5% is reported to be specific for TTP (George, 2009). Decreased
activity < 10% is suggestive but not specific for TTP. Gene mutations versus autoantibodies are still a consideration. Finally, both HUS and TTP can be triggered by autoimmune disease, so evaluation of antinuclear antibody, lupus anticoagulant, and antiphospholipid antibody are also important (Ariceta et al., 2009). Renal biopsy is not needed for diagnosis; however, it is sometimes undertaken, especially in severe renal failure or patients with recurrent disease. Disctinctive findings on biopsy may help differentiate HUS from TTP (Banerjee, 2009).
1120
K. WEBSTER AND E. SCHNITZLER
TREATMENT The mainstay of treatment for typical HUS is supportive care. Volume resuscitation, fluid and electrolyte monitoring, and transfusion of blood products are common, as is temporary need for dialysis (Lowe and Werner, 2005; Scheiring et al., 2008; Pomajzl et al., 2009). Treatment of neurologic manifestations is most often associated with control of seizure activity, with care to address any electrolyte imbalance as a potential cause.
Antibiotics Antibiotic therapy is necessary in infections due to Shigella or S. pneumoniae. In other causes of diarrheal HUS, there have been reports of worsened outcomes with antibiotic treatment. A meta-analysis of studies in which antibiotics were used was unable to demonstrate conclusively that harm occurs, although wide variation in treatments was observed (Safdar et al., 2002; Banerjee, 2009; Mohsin et al., 2010).
Cobalamin replacement In cases of cobalamin deficiency, supplementation may help to prevent future episodes (Banerjee, 2009). Unfortunately, despite therapy this disorder is often associated with progression of severe neurologic deficits due to the underlying homocysteine accumulation (Martinielli et al., 2011).
Plasma infusion and plasmapheresis Plasma infusion has been reported to be of benefit in some patients with atypical HUS or TTP. The goal of plasma infusion is to replace complement factors or ADAMTS13 enzyme that are deficient in the afflicted patient. In patients who have deficiencies, marked improvement is reported (Banerjee, 2009). Since many of these deficiencies may be caused not only by decreased production but by destruction via autoantibodies, plasma infusion alone may in some cases be harmful. HUS caused by pneumococcal infection (Banerjee, 2009) and by complement antibodies (Boyer et al., 2010) have both been worsened by plasma infusion. Because the underlying etiology is often unknown at the time of presentation, initial empiric therapy should be plasma exchange to remove the offending antibody. Plasma infusion may be useful in preventing recurrence, once the underlying deficiency has been identified (Kohli and Gulati, 2006; Loirat et al., 2010).
Immunotherapy Plasma exchange is likely to be effective in only 30–50% of patients with atypical HUS (Ariceta et al., 2009; Banerjee, 2009). Some patients may show an initial
response but this response is not sustained and/or repeated lifelong prophylactic treatment is needed. In such patients, reports of treatment with corticosteroids, vincristine, azathioprine, and cyclophosphamide have reported anecdotal success (Michael et al., 2009; Boyer et al., 2010). Often a combination of both immunosuppression and intermittent plasma exchange is necessary to sustain remission in severe relapsing forms of the disease. Inhibition of complement may be effective in aHUS due to complement protein deficiencies. Eculizumab and rituximab have been reported as effective therapies in both atypical HUS (Banerjee, 2009; Mache et al., 2009; Boyer et al., 2010; K€ose et al., 2010) and chronic relapsing TTP (Levandovsky et al., 2008). Currently, investigations are ongoing involving urtoxazumab, a targeted antibody therapy to neutralize Shiga toxin (Lopez et al., 2010). While this may help prevent the cascade of events leading to full HUS, the challenge will be providing therapy within 24–72 hours of exposure (Bitzan et al., 2010). Further investigation of this therapy is needed to provide more conclusive evidence of effect.
Transplantation Patients with aHUS may progress to renal failure and ultimately require transplantation. Unfortunately, as aHUS is most commonly associated with defective or deficient complement protein, the risk of disease recurrence or graft rejection is high (Cheong, 2009).
Complement therapy In variations of HUS associated with deficiency of complement regulatory proteins, replacement of these factors would be beneficial and more specific than plasma infusion alone. While no specific factor is currently available, work is ongoing to develop recombinant or concentrate of these important complement factors (Johnson and Taylor, 2008). Overall, the vast array of etiology and pathophysiology that underlies HUS creates a clinical challenge, with careful attention to presentation, family history, and diagnosis in order to achieve the proper diagnosis and therapy.
REFERENCES Ariceta G, Besbas N, Johnson S et al. (2009). Guideline for the investigation and initial therapy of diarrhea-negative hemolytic uremic syndrome. Pediatr Nephrol 24: 687–696. Bale JF Jr, Brasher C, Siegler RL (1980). CNS manifestations of the hemolytic-uremic syndrome. Relationship to
HEMOLYTIC UREMIC SYNDROME metabolic alterations and prognosis. Am J Dis Child 134: 869–872. Banerjee S (2009). Hemolytic uremic syndrome. Indian Pediatr 46: 1075–1084. Barit G, Sakarcan A (2005). Antibiotic resistant Streptococcus pneumoniae and hemolytic uremic syndrome. Eur J Pediatr 164: 414–416. Barnett ND, Kaplan AM, Bernes SM et al. (1995). Hemolytic uremic syndrome with particular involvement of basal ganglia and favorable outcome. Pediatr Neurol 12: 155–158. Bell BP, Griffin PM, Lozano P et al. (1997). Predictors of hemolytic uremic syndrome in children during a large outbreak of Escherichia coli O157:H7 infections. Pediatrics 100: E12. Besbas N, Karpman D, Landau D et al. (2006). A classification of hemolytic uremic syndrome and thrombotic thrombocytopenic purpura and related disorders. Kidney Int 70: 423–431. Bitzan M, Schaefer F, Reymond D (2010). Treatment of typical (enteropathic) hgemolytic uremic syndrome. Semin Thromb Hemost 36: 594–610. Bouts AH, Roofthooft MTR, Salomous GS et al. (2010). CD46-associated atypical hemolytic uremic syndrome with uncommon course caused by cblC deficiency. Pediatr Nephrol 25: 2547–2548. Boyer O, Balzamo E, Charbit M et al. (2010). Pulse cyclophosphamide therapy and clinical remission in atypical hemolytic uremic syndrome with anti-complement factor H autoantibodies. Am J Kidney Dis 55: 923–927. Brandt J, Wong C, Mihm S et al. (2002). Invasive pneumococcal disease and hemolytic uremic syndrome. Pediatrics 110: 371–376. ¨ et al. (2011). Hemolytic ureC¸altik A, Aky€ uz SG, Erdogan O mic syndrome triggered with a new pandemic virus: influenza A (H1N1). Pediatr Nephrol 26: 147–148. Centers for Disease Control and Prevention (2009). Morbidity and Mortality Weekly Report: Recommendations for diagnosis of Shiga toxin-producing Escherichia coli infections by clinical laboratories. October 16, 2009, Vol. 58, No. RR-12, pp. 1–14. Cerda J, Lameire N, Eggers P et al. (2008). Epidemiology of acute kidney injury. Clin J Am Soc Nephrol 3: 881–886. Chaturvedi S, Licht C, Langlois V (2010). Hemolytic uremic syndrome caused by Bordetella pertussis infection. Pediatr Nephrol 25: 1351–1364. Cheong H (2009). Can liver-kidney transplantation cure aHUS? Nephrology 5: 556–557. Cimolai N, Morrison BJ, Carter JE (1992). Risk factors for the central nervous system manifestations of gastroenteritisassociated hemolytic-uremic syndrome. Pediatrics 90: 616–621. Desch K, Motto D (2007). Is there a shared pathophysiology for thrombotic thrombocytopenic purpura and hemolyticuremic syndrome? J Am Soc Nephrol 18: 2457–2460. Dhuna A, Pascual-Leone A, Talwar D et al. (1992). EEG and seizures in children with hemolytic-uremic syndrome. Epilepsia 33: 482–486. DiMario FJ Jr, Br€onte-Stewart H, Sherbotie J et al. (1987). Lacunar infarction of the basal ganglia as a complication
1121
of hemolytic-uremic syndrome: MRI and clinical correlations. Clin Pediatr 25: 586. Eriksson KJ, Boyd SG, Tasker RC (2001). Acute neurology and neurophysiology of haemolytic-uraemic syndrome. Arch Dis Child 84: 434–435. Gasser C, Gautier E, Steck A et al. (1955). Hemolytic-uremic syndrome: bilateral necrosis of the renal cortex in acute acquired hemolytic anemia. Schweiz Med Wochenschr 85: 905–909. George JN (2009). The thrombotic thrombocytopenic purpura and hemolytic uremic syndromes: overview of pathogenesis (experience of the Oklahoma TTP-HUS Registry, 1989–2007). Kidney Int 75 (Suppl 112): S8–S10. Glatstein M, Miller E, Garcia-Boumissen F et al. (2010). Timing and utility of ultrasound in diarrhea-associated hemolytic uremic syndrome: 7-year experience of a large tertiary care hospital. Clin Pediatr 49: 318. Gould LH, Demma L, Jones TF et al. (2009). Hemolytic uremic syndrome and death in persons with Escherichia coli O157:H7 infection, Foodborne Diseases Active Surveillance Network Sites, 2000–2006. Clin Infect Dis 49: 1480–1485. Hahn JS, Havens PL, Higgins JJ et al. (1989). Neurological complications of hemolytic-uremic syndrome. J Child Neurol 4: 108–113. Hinchey J, Chaves C, Appigani B et al. (1996). A reversible posterior leukoencephalopathy syndrome. N Engl J Med 334: 494. Johnson S, Taylor CM (2008). What’s new in haemolytic uraemic syndrome? Eur J Pediatr 167: 965–971. Johnson S, Taylor CM (2009). In: ED Ainer, D Ellis (Eds.), Pediatric Nephrology. 6th edn. Springer, pp. 1155–1180. Karpman D, Sartz L, Johnson S (2010). Pathophysiology of typical hemolytic uremic syndrome. Semin Thromb Hemost 36: 575–585. Kavanagh D, Richards A, Fremeaux-Bacchi V et al. (2007). Screening for complement system abnormalities in patients with atypical hemolytic uremic syndrome. Clin J Am Soc Nephrol 2: 591–596. Kohli R, Gulati S (2006). Plasma infusion therapy in atypical hemolytic uremic syndrome – long term outcome. Indian Pediatr 43: 164–166. ¨ , Zimmerhackl L-B, Jungraithmayr T et al. (2010). New K€ ose O treatment options for atypical hemolytic uremic syndrome with the complement inhibitor eculizumab. Semin Thromb Hemost 36: 669–672. Lei T-H, Hsia S-H, Wu C-T et al. (2010). Streptococcus pneumoniae-associated haemolytic uremic syndrome following influenza A virus infection. Eur J Pediatr 169: 237–239. Levandosky M, Harvey D, Lara P et al. (2008). Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS): a 24-year clinical experience with 178 patients. J Hematol Oncol 1: 23 http://www.jhoonline.org/ content/1/1/23. Loirat C, Noris M, Fremeaux-Bacchi V (2008). Complement and the atypical hemolytic uremic syndrome in children. Pediatr Nephrol 123: 1957–1972.
1122
K. WEBSTER AND E. SCHNITZLER
Loirat C, Garnier A, Sellier-Leclerc A-L et al. (2010). Plasmatherapy in atypical hemolytic uremic syndrome. Semin Thromb Hemost 36: 673–681. Lopez EL, Contrini MM, Glatstein E et al. (2010). Safety and pharmacokinetics of urtoxazumab, a humanized monoclonal antibody, against Shiga-like toxin 2 in healthy adults and in pediatric patients infected with Shiga-like toxin-producing Escherichia coli. Antimicrob Agents Chemother 54: 239–243. Lowe EJ, Werner EJ (2005). Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome in children and adolescents. Semin Thromb Hemost 31: 717–729. Mache CJ, Acham-Roschitz B, Fremeaux-Bacchi V et al. (2009). Complement inhibitor eculizumab in atypical hemolytic uremic syndrome. Clin J Am Soc Nephrol 4: 1312–1316. Martinelli D, Deodato F, Dionisi-Vici C (2011). Cobalamin C defect: natural history, pathophysiology, and treatment. J Inherit Metab Dis 34: 127–135. Melmann A, Fruth A, Friedrich AW et al. (2009). Phylogeny and disease association of Shiga toxin-producing Escherichi coli O91. Emerg Infect Dis 15: 1474–1477. Michael M, Elliott EJ, Craig JC et al. (2009). Interventions for hemolytic uremic syndrome and thrombotic thrombocytopenic purpura: a systematic review of randomized controlled trials. Am J Kidney Dis 53: 259–272. Moake JL (2002). Thrombotic microangiopathies. N Engl J Med 347: 589–600. Mohsin M, Haque A, Ali A et al. (2010). Effects of ampicillin, gentamicin, and cefotaxime on the release of Shiga toxins from Shiga toxin-producing Escherichia coli isolated during a diarrhea episode in Faisalabad, Pakistan. Foodborne Pathog Dis 7: 85–90. Nakahata T, Tanaka H, Tateyama T et al. (2001). Thrombotic stroke in a child with diarrhea-associated hemolytic-uremic syndrome with a good recovery. Tohoku J Exp Med 193: 73–77. Nolasco LH, Turner NA, Bernardo A et al. (2005). Hemolytic uremic syndrome-associated Shiga toxins promote endothelial-cell secretion and impair ADAMTS13 cleavage of unusually large von Willebrand factor multimers. Blood 106: 4199–4209. Ogura H, Takaoka M, Kishi M et al. (1998). Reversible MR findings of hemolytic uremic syndrome with mild encephalopathy. AJNR Am J Neuroradiol 19: 1144–1145. Pomajzl RJ, Varman M, Holst A et al. (2009). Hemolytic uremic syndrome (HUS) – incidence and etiologies at a regional Children’s Hospital in 2001–2006. Eur J Clin Microbiol Infect Dis 28: 1431–1435. Printza N, Roilides E, Kotsiou M et al. (2011). Pandemic influenza A (H1N1) 2009-associated hemolytic uremic syndrome. Pediatr Nephrol 26: 143–144. Qamar IU, Ohali M, MacGregor DL et al. (1996). Long-term neurological sequelae of hemolytic-uremic syndrome: a preliminary report. Pediatr Nephrol 10: 504–506.
Quintrec ML, Roumenina L, Noris M et al. (2010). Atypical hemolytic uremic syndrome associated with mutations in complement regulator genes. Semin Thromb Hemost 36: 641–652. Razzaq S (2006). Hemolytic uremic syndrome: an emerging health risk. Am Fam Physician 74: 991–996. Rivero MA, Passucci JA, Rodriguez EM et al. (2010). Role and clinical course of verotoxigenic Escherichia coli infections in childhood acute diarrhoea in Argentina. J Med Microbiol 59: 345–352. Rooney JC, Anderson RM, Hopkins IJ (1971). Clinical and pathologic aspects of central nervous system involvement in the haemolytic uraemic syndrome. Proc Aust Assoc Neurol 8: 67–75. Ruggenenti P, Noris M, Remuzzi G (2001). Thrombotic microangiopathy, hemolytic uremic syndrome, and thrombotic thrombocytopenic purpura. Kidney Int 60: 831–846. Rust R, Chun R (1999). Interrelationships between renal and neurologic diseases and therapies. In: KF Swaiman, S Ashwal (Eds.), Pediatric Neurology Principles and Practice. 3rd edn. Mosby, St Louis, pp. 1403–1437. Rust RS, Worrel TE (2009). Hemolytic uremic syndrome. eMedicine Neurology 1–30. Safdar N, Said A, Gangon RE et al. (2002). Risk of hemolytic uremic syndrome after antibiotic treatment of Escherichia coli O157:H7 enteritis: a meta-analysis. JAMA 288: 996–1001. Scheiring J, Andreoli SP, Zimmerhackl LB (2008). Treatment and outcome of Shiga-toxin-associated hemolytic uremic syndrome. Pediatr Nephrol 23: 1749–1760. Scheiring J, Rosales A, Zimmerhackl LB (2010). Today’s understanding of the haemolytic uraemic syndrome. Eur J Pediatr 169: 7–13. Schlieper A, Orrbine E, Wells GA et al. (1999). Neuropsychological sequelae of haemolytic uraemic syndrome. Arch Dis Child 80: 214–220. Schneppenheim R, Budde U, Hassenpflug W et al. (2004). Severe ADAMTS-13 deficiency in childhood. Semin Hematol 41: 83–89. Sebire G, Husson B, Lasser C et al. (1995). Encephalopathy induced by arterial hypertension: clinical, radiological and therapeutic aspects. Arch Pediatr 2: 513. Sharma J, Bharadawa K, Shah K et al. (1993). Plasmodium vivax malaria presenting as hemolytic-uremic syndrome. Indian Pediatr 30: 369–371. Sharma AP, Greenberg CR, Prasad AN et al. (2007). Hemolytic uremic syndrome secondary to cobalamin C C (Cb1c) disorder. Pediatr Nephrol 22: 2097–2103. Sheth KJ, Swick HM, Haworth N (1986). Neurological involvement in hemolytic-uremic syndrome. Ann Neurol 19: 90–93. Steinberg A, Ish-Horowitcz M, el-Peleg O et al. (1986). Stroke in a patient with hemolytic-uremic syndrome with a good outcome. Brain Dev 8: 70–72.
HEMOLYTIC UREMIC SYNDROME Steinborn M, Leiz S, R€ udisser K et al. (2004). CT and MRI in haemolytic uraemic syndrome with central nervous system involvement: distribution of lesions and prognostic value of imaging findings. Pediatr Radiol 34: 805–810. Stewart CL, Tina LU (1993). Hemolytic uremic syndrome. Pediatr Rev 14: 218–224.
1123
Toldo I, Manara R, Cogo P et al. (2009). Diffusion-weighted imaging findings in hemolytic uremic syndrome with central nervous system involvement. J Child Neurol 24: 247–250. Upadhyahya K, Barwick K, Fishaut M et al. (1980). The importance of non-renal involvement in hemolytic uremic syndrome. Pediatrics 65: 115–120.
Chapter 75
Hemolytic uremic syndrome 1
KATHLEEN WEBSTER1* AND EUGENE SCHNITZLER2 Department of Pediatrics, Loyola University Medical Center, Maywood, IL, USA
2
Department of Neurology, Loyola University Medical Center, Maywood, IL, USA
INTRODUCTION The terms “microangiopathic hemolytic anemia” and “thrombotic microangiopathy” have been used to describe disorders consisting of endothelial cell damage, thrombosis, and resulting thrombocytopenia and red cell destruction. Two important causes of these findings are hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP). Both disorders can lead to widespread organ damage and predominantly affect the brain and kidney. In TTP, renal disease is less common and neurologic involvement is more pronounced. Although TTP is more commonly reported in adults and HUS in children, there have been reported cases of each disorder occurring outside of the typical age ranges and both should be considered in the appropriate clinical setting (Moake, 2002).
DEFINITION HUS was first described by Gasser and colleagues in 1955. It is defined by the triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure (Eriksson et al., 2001; Scheiring et al., 2008; Johnson and Taylor, 2009; Michael et al., 2009). Typical (D þ) HUS follows within 2 weeks of an acute diarrheal illness. Atypical (or D ) HUS has also been reported and accounts for 10–20% of reported cases. Potential etiologies of atypical HUS include complement deficiency, inborn errors of metabolism, medications, infectious agents, and autoimmune disease processes (Table 75.1). The distinction between these two types can be important with regards to etiology, pathogenesis, long-term course, and treatment. Atypical HUS (aHUS) is associated with an increased risk of seizures and other
neurologic complications (Johnson and Taylor, 2009; Michael et al., 2009; Scheiring et al., 2010).
EPIDEMIOLOGYAND ETIOLOGY Although HUS is most commonly known as a leading cause of acute renal failure in children (Cerda et al., 2008), other organ systems have also been reported to be affected, particularly the central nervous system (CNS) (Eriksson et al., 2001; Banerjee, 2009; Scheiring et al., 2010). It is reported that up to half of children with HUS will have CNS involvement, most commonly in the form of seizures, altered mental status, or coma. HUS is estimated to occur with a frequency of 0.3–3.3 per 100 000 children worldwide, although it is noted that the incidence has been increasing in the past decade (Eriksson et al., 2001; Pomajzl et al., 2009). The most commonly affected age groups are children less than 5 years old, accounting for 50–70% of cases, and adolescents. Infants have rarely been reported to be affected. Up to 40% of children may require critical care support. Mortality from HUS is 2– 7%, with higher risk seen in females, children under 5 years of age, the elderly, and patients with atypical or recurrent HUS (Gould et al., 2009; Rust and Worrel, 2009). In both typical HUS and aHUS, early presentation of CNS symptoms is associated with a less favorable outcome (Rust and Worrel, 2009; Scheiring et al., 2010).
Typical hemolytic uremic syndrome The typical presentation of HUS occurs following a diarrheal prodrome. Diarrhea is infectious, usually due to Shiga toxin-producing Escherichia coli (STEC) (Ruggenenti et al., 2001; Michael et al., 2009). Although the 0157:H7 subtype of E. coli is the most commonly identified in the US, other subtypes have been found (Centers for Disease Control, 2009; Melmann et al., 2009). Of
*Correspondence to: Kathleen Webster, M.D., Loyola University Medical Center, 2160 S 1st Avenue, Maywood, IL 60153, USA. Tel: þ1-708-327-9137, Fax: þ1-708-216-5602, E-mail: [email protected]
1114
K. WEBSTER AND E. SCHNITZLER
Table 75.1 Etiologies of atypical hemolytic uremic syndrome Infectious
Noninfectious
STEC infection Diarrheal
Complement deficiency Cobalamin metabolism deficiency Malignancy Transplant SLE Antiphospholipid syndrome Pregnancy HELLP syndrome Medication-induced Quinine Oral contraceptives Immunosuppressants Tacrolimus Ciclosporin Mycophenolate
Urinary Other diarrheal infections Shigella Citrobacter Yersinia Clostridium difficile Giardia Viral infections HIV H1N1 influenza A CMV EBV Other infections Pertussis Malaria Pneumococcal
STEC, Shiga toxin-producing Escherichia coli; HIV, human immunodeficiency virus; CMV, cytomegalovirus; EBV, Epstein–Barr virus; SLE, systemic lupus erythematosus; HELLP, hypertension, elevated liver enzymes, low platelets.
note, although E. coli 0157:H7 is well known as the cause of HUS, only 8% of persons with diarrheal illness due to this organism go on to develop HUS. Other infectious causes of diarrhea have been identified in afflicted patients, including Shigella, Citrobacter, Yersinia, Clostridium difficile and Giardia (Besbas et al., 2006; Pomajzl et al., 2009). STEC associated HUS accounts for up to 90% of cases and follows a seasonal pattern with higher incidence in summer and fall. Food-borne outbreaks have been reported and may be associated with raw ground beef, unpasteurized juice or milk, fresh produce such as lettuce, spinach, and alfalfa sprouts, and contaminated water (Razzaq, 2006; Rivero et al., 2010). The bacteria may be easily spread, and infection may be acquired from contact with animals and their environment, or other infected persons. In cases of multiple family members with symptoms it is important to distinguish concurrent HUS with diarrheal symptoms from asynchronous events, which may be related to genetic causes or complement deficiencies (Centers for Disease Control, 2009; Pomajzl et al., 2009).
Atypical hemolytic uremic syndrome Atypical HUS (aHUS) is being described in a growing body of literature and is more commonly associated with
neurologic sequelae. In addition to diarrheal infections, HUS may be triggered by STEC infection of the urinary tract. Viral infections may also be associated with HUS. Reported cases have involved human immunodeficiency virus (HIV), novel H1N1 influenza A, cytomegalovirus (CMV), Epstein–Barr virus (EBV), and others (Ariceta et al., 2009; Banerjee, 2009; Printza et al., 2011; C¸altik et al., 2011). There are also several case reports of infants with HUS related to pertussis (Chaturvedi et al., 2010). Sharma et al. (1993) reported HUS following malaria. Another notable infectious cause is bacteremia, meningitis, or empyema due to Streptococcus pneumoniae. This particularly virulent form of HUS mainly affects children under 2 years of age and is associated with a much higher mortality (Brandt et al., 2002; Barit and Sakarcan, 2005; Besbas et al., 2006; Lei et al., 2010; Scheiring et al., 2010). Atypical HUS is most commonly related to noninfectious causes. Over 50% of cases are attributed to congenital or acquired complement deficiency, notably disorders of factor H, factor I, factor B, and membrane cofactor protein (MCP) (Quintrec et al., 2010). Abnormal processing of cobalamin (vitamin B12) leading to severe deficiency is an inborn error of metabolism and well described as an etiology of a particularly severe form of HUS with a high rate of neurologic symptoms (Sharma et al., 2007). Other reported associations with atypical HUS are malignancies, chemotherapy, systemic lupus erythematosis (SLE), antiphospholipid syndrome, pregnancy, and HELLP syndrome, and with medications such as quinine or oral contraceptives (Besbas et al., 2006; Michael et al., 2009; Scheiring et al., 2010). Patients who have had solid organ or bone marrow transplant also seem to be more susceptible to development of HUS. It is unclear whether this is due to the transplant state itself or due to immunosuppressive medications, such as tacrolimus, ciclosporin, and mycophenolate (Ariceta et al., 2009; Banerjee, 2009). In many of the atypical cases of HUS, it has been proposed that both a genetic predisposition and an environmental trigger are required to produce disease (Johnson and Taylor, 2008).
Thrombotic thrombocytopenic purpura The presentation of HUS is closely related to thrombotic thrombocytopenic purpura (TTP). Like HUS, TTP is associated with microangiopathic hemolytic anemia and thrombocytopenia. The initial description of TTP by Moschowitz in 1925 reported a “pentad” of these two findings in addition to fever, neurologic impairment, and renal dysfunction. As in HUS, platelet aggregation occurs, although the etiology in TTP is deficiency of a protease known as ADAMTS13. This deficiency
HEMOLYTIC UREMIC SYNDROME may be congenital, known as Upshaw–Schulman disease, with presentation occurring early in childhood, even in infancy (Schneppenheim et al., 2004; Lowe and Werner, 2005). Acquired deficiency may be related to autoantibodies against ADAMTS13 and present later in life, triggered by medications, collagen vascular disease, or infection. Untreated, the mortality of TTP is over 90%, although with plasma therapy, the incidence of mortality drops to 10–20%. In the current literature, there is disagreement as to whether TTP is a distinct syndrome from HUS, or whether these two disorders represent a spectrum of disease. HUS is classically thought of as a renal disease with systemic effects, while TTP is considered as a systemic disease with effects on the central nervous system and kidney (Desch and Motto, 2007). Often the two disorders are difficult to distinguish based on clinical presentation alone and further testing of complement and genetic factors is required to make a definitive diagnosis. Many of the same medications and diseases can trigger TTP and atypical HUS (Nolasco et al., 2005; Desch and Motto, 2007). It remains to be seen whether these two disorders will be found to be more similar or more distinct as the pathophysiology continues to be explored.
PATHOPHYSIOLOGY As described above, a wide range of etiologies of typical and atypical HUS and TTP are reported. Although each of these results in a common clinical picture, the pathophysiology of each is distinct.
Typical hemolytic uremic syndrome In STEC-associated HUS, the infecting organism enters the gastrointestinal tract and binds to and causes inflammation of the intestinal epithelium (Pomajzl et al., 2009). The bacteria produce a toxin, called Shiga toxin (Stx) or verotoxin. The toxin enters the bloodstream, bound to a carrier such as monocytes, neutrophils, or platelets. The toxin binds to the globotriaosyl ceramide (Gb3) receptor. The toxin results in red cell lysis and damage to vascular endothelium. This in turn leads to a cascade of microthrombosis, platelet activation, and thrombotic injury to the vasculature (Lowe and Werner, 2005; Karpman et al., 2010; Scheiring et al., 2010).
Atypical hemolytic uremic syndrome Atypical HUS may be caused by a variety of etiologies, each with a different trigger resulting in the final common pathway of inflammatory cascade causing renal endothelial and vascular injury and resultant thrombotic microangiopathy. Up to 50% of patients may have chromosome 1 mutations or autoantibody production leading
1115
to deficiency and dysregulation of the complement cascade (Loirat et al., 2008; Banerjee, 2009). Another mutation on chromosome 1 may lead to deficient processing of cobalamin (vitamin B12). This leads to a defect in the processing of cobalamin, with associated homocystinuria and methylmalonic academia (Sharma et al., 2007; Banerjee, 2009; Bouts et al., 2010; Martinelli et al., 2011). This form of aHUS usually presents in infancy and is associated with significant neurologic manifestations including hypotonia, lethargy, feeding difficulties and failure to thrive (Ariceta et al., 2009). Finally, pneumococcal infection may lead to production of neuraminidase, which exposes a protein known as Thomsen-Friedenreich antigen (TF-Ag) on renal endothelial cells, and causing immune activation (Banerjee, 2009; Bouts et al., 2010).
CLINICAL MANIFESTATIONS In typical HUS, the history may include exposure to contaminated food. Symptoms generally develop 1–8 days following ingestion of the offending agent. Clinically the child usually presents with bloody diarrhea and cramping abdominal pain. Physical examination may show petechiae and/or mucosal bleeding. Diagnostic criteria include anemia, thrombocytopenia, and elevated creatinine. An “incomplete” HUS has been described in children who present with bloody diarrhea, anemia, and thrombocytopenia but have mild or absent elevation of creatinine and do not go on to develop overt renal failure (Lowe and Werner, 2005; Besbas et al., 2006; George, 2009; Scheiring et al., 2010). The differential diagnosis includes sepsis and disseminated intravascular coagulation (DIC), SLE, and TTP. Of note, in both HUS and TTP, other markers of coagulation including PT and aPTT are normal, thus distinguishing these from DIC. Since the anemia is due to hemolysis, the peripheral blood smear will often reveal schistocytes and helmet cells (Lowe and Werner, 2005). Most HUS will have a negative direct Coombs test, with the notable exception of that following S. pneumoniae infection, in which up to 90% may be positive (Banerjee, 2009; Scheiring et al., 2010).
NEUROLOGIC FINDINGS AND SEQUELAE CNS involvement occurs in 20–50% of patients with hemolytic uremic syndrome and is usually seen within the first week of illness (Bale et al., 1980). CNS symptoms may be mild with many patients demonstrating only irritability and lethargy. More severe CNS presentation may be manifested by seizures, stupor, coma, and hemiparesis. Aphasia, ataxia, chorea, dystonia, and visual disturbances may also occur (Hahn et al., 1989). Cerebral edema with headache, vomiting, papilledema,
1116 K. WEBSTER AND E. SCHNITZLER sixth nerve weakness, and altered mental status is comand hearing loss. Dialysis is frequently used as a treatmonly observed. HUS presenting with early CNS signs ment modality for HUS and is associated with improved and symptoms is associated with higher rates of mortalsurvival and prevention of encephalopathy (Stewart and ity as well as neurologic and non-neurologic sequelae Tina, 1993); however, dialysis itself may cause neuro(Upadhyahya et al., 1980). logic abnormalities. Headache is commonly observed The etiology of CNS pathophysiology in HUS is mulduring dialysis in adults, adolescents, and older children. tifactorial but underlying mechanisms closely parallel Headaches may be migraine variants or secondary to those attributed to acute renal failure (ARF). ARF has water intoxication or hypertension. Headache is also a been known to be associated with altered mental status component of the dialysis disequilibrium syndrome for more than a century. Although a significant degree which also includes mental status changes, fatigue, of renal failure can be tolerated without neurologic and muscle cramps. In more severe cases of dialysis diseffects, rapid deterioration of kidney function such as equilibrium syndrome, seizures and coma may develop. occurs in HUS is more likely to result in precipitous alterDialysis disequilibrium syndrome tends to occur early in ation of neurologic status (Eriksson et al., 2001). the course of dialysis and as a complication of rapid dialThe neurologic deterioration seen in HUS with ARF ysis. The underlying pathophysiology is incompletely relates to uremia, hypertension, and altered fluid and understood but seems to be secondary to cerebral edema electrolyte metabolism. Water intoxication is seen early produced by osmotic gradients of urea and other osmotin the course of ARF and is accompanied by hyponatreically active compounds (Rust and Chun, 1999). mia. Early clinical signs of water intoxication include Although hypertension, dialysis equilibrium synheadache and altered mental status which can progress drome, and the metabolic changes of ARF account for rapidly to seizures and coma. Uremia in HUS is primarily a significant proportion of the CNS pathophysiology due to glomerular injury resulting in failure of excretion seen in HUS, other factors appear to be involved. of toxic catabolites of protein. This is accompanied by Dhuna et al. (1992) reported a series of 11 children with acidosis with an increased ion gap, bicarbonate wasting, HUS and seizures. Generalized seizures occurred in four and elevated serum potassium levels. Early uremic patients and partial seizures in seven patients. The chilencephalopathy is characterized by subtle changes in dren with generalized seizures had diffuse slowing on mental status including irritability, inattentiveness, conEEG and normal CT scans of the brain. All four children fusion, memory lapses, lack of interest, fatigue, speech had a normal outcome. However, in the patients with dyspraxia, and mild cognitive impairment. These symppartial seizures, there was diffuse slowing, but focal toms may be followed by movement disorders, particuslowing, focal spikes, asynchronous slowing, and burst larly tremor, tetany, and asterixis. Primitive reflexes suppression patterns were also noted. Six of the seven such as snouting and rooting sometimes occur. Hemiparpatients with focal seizures had clinical findings of hemiesis and transient loss of vision and hearing have also paresis. CT scans in these six patients demonstrated been noted. Uremia may also produce generalized weakstrokes primarily in the basal ganglia and thalamus. ness secondary to neuropathy (Rust and Chun, 1999). All six patients recovered with residual hemiparesis. Seizures occur in up to 40% of children with uremia Thus, partial seizures in HUS were correlated with focal secondary to HUS. These are usually generalized but EEG changes and structural pathology. Strokes secondmay also be focal or myoclonic. Hypertension due to ary to infarctions and microinfarctions seemed to ARF also typically results in an encephalopathy characaccount for these structural findings. terized by generalized seizures as well as headache and Sheth and associates (1986) reviewed 44 children with visual changes. Focal findings including aphasia, hemiHUS seen between 1972 and 1984. Fifteen patients had paresis and particularly sixth nerve palsies have been neurologic complications including 12 who had seizures. described. Occipital blindness is common with hypertenStatistically significant correlations were noted between sive encephalopathy of various etiologies including CNS involvement and metabolic abnormalities including ARF. This is referred to as “reversible posterior leukoenhypocalcemia, hypocapnia, and elevated serum creaticephalopathy” or “occipital-parietal encephalopathy.” nine levels. CSF protein was elevated in four patients, Correlating magnetic resonance imaging (MRI) and but there were none with CSF pleocytosis or decreased computed tomography (CT) findings of white matter CSF glucose. Only six patients with CNS involvement edema without infarction have been noted to accompany recovered completely. Three patients died and six had the clinical loss of vision (Sebire et al., 1995; Hinchey neurologic and/or renal residuals or hypertension. Postet al., 1996). mortem examination of one patient who died showed Early dialysis is effective in prevention and reduction probable cerebral edema but no findings of any vascular of symptoms of uremic encephalopathy as well as microthrombi. Eriksson et al. (2001) summarized EEG improving outcomes in cases of uremic neuropathy data in 22 patients with HUS. They noted that patients
HEMOLYTIC UREMIC SYNDROME 1117 with periodic activity as well as focal and multifocal epineurologic involvement does not necessarily imply poor leptogenic activity had higher rates of mortality, epiprognosis and that basal ganglia involvement in particulepsy, and neurologic sequelae. In particular, focal lar is often associated with full recovery or only mild occipital and temporal slowing and epileptiform disresiduals. Favorable outcome following CNS involvecharges were correlated with residuals of vision impairment even with thrombotic strokes has also been ments and complex partial seizures. The majority of reported by others (Steinberg et al., 1986; Ogura et al., patients with only generalized slowing on EEG recovered 1998; Nakahata et al., 2001). without neurologic complications. Predilection for basal ganglia involvement in HUS Rooney et al. (1971) reported a series of postmortem was corroborated by Steinborn et al. (2004). They neuropathologic findings in HUS patients and did not reviewed MRI and CT scans in 10 patients with HUS describe any unique markers for the disorder. They who had significant CNS involvement. Some 60% had noted cerebral edema and hypoxic changes. In contrast imaging abnormalities in the basal ganglia. AbnormaliUpadhyaya and associates (1980) reviewed 15 patients ties were also seen in the brainstem, cerebellum, and with HUS, three of whom died. Microthrombi were thalami. These signal changes were suggestive of microfound in the kidneys and lungs in all three patients but infarctions. The authors concluded that the basal ganglia also in the brain in two out of the three deceased patients. are commonly affected in HUS and a direct toxic effect The authors speculated that nonrenal multiple organ of verotoxin was again postulated. Furthermore the microthrombi formation seemed to correlate with a imaging findings were often reversible and did not more fulminant course in patients with HUS. necessarily imply an adverse outcome. The presence In a 1980 series, by Bale et al., of 60 patients with HUS, of hemorrhage in a lesion seemed to correlate with subhalf had encephalopathy and/or seizures. CNS involvesequent gliotic or cystic MRI findings as well as residual ment was correlated with azotemia, hyponatremia, and neurologic dysfunction. Two of the MRIs in this series the need for dialysis. Coma on admission and elevated of patients also included diffusion-weighted imaging CSF protein were associated with subsequent mortality (DWI). A case with DWI demonstrating basal ganglia and neurologic morbidity. Only one patient died and lesions was also described by Toldo and associates was autopsied. No microthrombi were seen in the brain. (2009). DWI may be more sensitive in determining neuOnly edema and anoxic changes were noted. rologic prognosis in that reduced apparent diffusion Neuroimaging with CT and MRI has proven to be coefficient (ADC) may correlate with irreversible valuable in the diagnosis, treatment, and prognosis of lesions. A summary of the clinical EEG and neuroimagHUS. Hahn and associates (1989) reported 78 children ing findings in HUS is found in Table 75.2. with HUS; 16 had neurologic complications. CT scans The neuropsychological prognosis of children survivshowed cerebral edema in four patients, large vessel ing HUS has generally been favorable even in patients infarctions in four patients, and multiple hemorrhages who had coma and seizures. Qamar and associates in one patient. At autopsy of three patients, cerebral (1996) reviewed the long-term neurologic and psychoeedema was found but no microthrombi or large vessel ducational outcomes of seven children who had experithrombi were noted. In one patient there was a large enced at least one seizure during their acute presentation hemorrhagic infarction. with HUS. Three children had normal neurologic examIn 1987, DiMario et al. first reported a lacunar infarcinations but four demonstrated mild neurologic abnortion in the basal ganglia as a complication of HUS in a 5malities such as clumsiness, fine motor deficits, year-old girl. Following initial presentation with mild hyperactivity, and distractibility. However, in-depth psyencephalopathy, she developed a left hemiparesis. chometric studies revealed normal IQ scores and behavMRI demonstrated increased T1- and T2-weighted ioral indices in all seven children. In a Canadian images in the consistent with a subacute hemorrhagic multicenter study of 91 case control pairs, Schlieper infarction in the right caudate and lentiform nuclei. and associates (1999) found no significant impact on Barnett and associates (1995) presented two additional cognitive skills, learning, or academic achievement meacases with HUS complicated by coma and dystonic possured at least 6 months after the acute episode of HUS. A turing. MRI and CT scans showed signal changes in the subtle but significant effect of severity of HUS as meabasal ganglia bilaterally. The authors reviewed the litersured by serum creatinine was correlated with lower ature on eight other patients with basal ganglia involvescores on subtests of verbal abilities. However, the inciment. They postulated possible etiologies including dence of attention deficit disorder was no higher in surmicrothrombi secondary to endothelial cell damage vivors of HUS than in age-matched controls. and/or direct effects of the enteric verotoxin. Since the Cimolai and associates (1992) reviewed the risk facmajority of patients recovered, the authors hypothesized tors associated with CNS involvement in HUS in 91 a reversible process. Furthermore they noted that patients. They concluded that younger age and prior
1118
K. WEBSTER AND E. SCHNITZLER
Table 75.2 Clinical EEG and neuroimaging findings in hemolytic uremic syndrome with central nervous system involvement Clinical findings Mild CNS involvement
Prognosis: favorable for recovery
Irritability, lethargy, headache, altered mental status
EEG
CT, MRI
Normal, mild diffuse slowing
Normal, mild cerebral edema
Clinical findings Severe CNS involvement
Prognosis: variable, increased mortality and neurological sequelae
Seizures, stupor, coma, hemiparesis, aphasia, movement disorders, papilledema, visual disturbances, sixth nerve palsy
EEG
CT, MRI
Diffuse slowing, focal slowing, asynchronous slowing, focal spikes burst suppression
Reversible posterior leukoencephalopathy. Infarction and micro-infarctions, primarily in the basal ganglia and thalamus
treatment with gastrointestinal antimotility drugs led to a higher risk of development of HUS in patients infected with Escherichia coli 0157:H7. Using multivariate analysis significant CNS risk factors included female gender, prolonged use of an antimotility drug, and increased hemoglobin levels. Conversely, prior treatment with blood products was associated with a lower risk of neurologic findings. The increased risk factor of female gender applied only to presentation with encephalopathy but not to seizures. The antimotility drugs included opium, codeine, loperamide, diphenoxylate, and anticholinergics. The association of gastrointestinal antimotility agents suggests several possible etiologic mechanisms including more prolonged gastrointestinal absorption of verotoxin. In addition these agents may have direct CNS toxicity which might be further enhanced by impaired renal excretion. It should also be noted that these agents are no longer routinely prescribed by pediatricians for the treatment of diarrhea in infants and young children (Bell et al., 1997).
DIAGNOSIS Diagnosis of typical HUS is usually made clinically based on history and laboratory findings (Table 75.3) (Levandosky et al., 2008; Johnson and Taylor, 2009). All children with diarrheal HUS should have culture of the
stool performed. E. coli 0157:H7 is identified by growth on selective agar within 24 hours. Further testing with PCR or EIA may be done. Although these tests are rapid, they are best performed on colonies already isolated on a culture plate, or from enriched broth that has been incubated. Therefore the earliest confirmed diagnosis still requires 24–36 hours to complete (Centers for Disease Control, 2009). In addition to stool, urine culture for STEC has been reported to be positive, even in the absence of diarrhea. Abdominal ultrasound may be useful in diagnosis during the prodromal phase by identifying thickening of large bowel wall and echogenicity of renal parenchyma (Glatstein et al., 2010). In atypical HUS, a risk factor or deficiency can be identified in approximately 60% of cases (Ariceta et al., 2009). Bacterial culture may help to identify pneumococcal infection as a trigger. For all other causes, serum testing may be of use. Due to the wide range of testing and expense and length of time to diagnosis, a prioritized and stepwise approach to diagnosis is recommended (Table 75.4); however, if therapy with plasma infusion or pheresis is being considered, it is necessary to obtain serum samples prior to initiation of therapy (Banerjee, 2009) or wait a minimum of 2 weeks following plasma infusion (Kavanagh et al., 2007). The most common etiology of atypical HUS is complement deficiency (Besbas et al., 2006; Ariceta et al., 2009). Serum
HEMOLYTIC UREMIC SYNDROME
1119
Table 75.3 Diagnosis of typical hemolytic uremic syndrome History
Laboratory study
Diarrhea within past 2 weeks Age > 6 months Endemic area Exposure to contaminated food Abrupt onset Single episode Concurrent affected contact
Classic features Chemistry panel CBC Hemolytic studies Peripheral smear
Etiologic studies Stool culture Selective agar for E. coli 0157 Serotyping of isolates PCR for Stx1, Stx2
LDH Haptoglobin Coagulation studies PT, PTT Fibrinogen D-dimer Red cell production Reticulocyte count
Findings
Elevated BUN Elevated creatinine Anemia Thrombocytopenia Schistocytes Helmet cells Burr cells Elevated Decreased
Normal Normal Elevated Elevated
PCR, polymerase chain reaction; Stx, Shiga toxin; CBC, complete blood count; LDH, lactate dehydrogenase; PT, prothrombin time; PTT, partial thromboplastin time; BUN, blood urea nitrogen.
Table 75.4 Approach to diagnostic and etiologic work-up in atypical hemolytic uremic syndrome Clinical factor
Possible etiology
Suggested testing
Meningitis, pneumonia
Pneumococcal infection
Age < 6 months, failure to thrive, neurologic symptoms Other atypical HUS
Deficient cobalamin metabolism
Culture of affected site Direct Coombs test Urine and serum amino acids C3, C4 levels Factor H, B, I levels MCP expression ADAMTS13 activity
Neurologic symptoms, family history, insidious onset
Complement deficiency
TTP
HUS, hemolytic uremic syndrome; TTP, thrombotic thrombocytopenic purpura; MCP, membrane cofactor protein; ADAMTS13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13.
assays for levels of C3 along with complement factors H, I and B and MCP should be obtained. If a low level is found, genetic testing or autoantibody assays may also be considered (Kavanagh et al., 2007). In children with coexisting failure to thrive and prominent neurologic symptoms, assessment of urine and serum amino acids may reveal congenital cobalamin deficiency (Ariceta et al., 2009; Banerjee, 2009). For patients in whom TTP is suspected, activity of the enzyme ADAMTS13 may be analyzed. Activity < 5% is reported to be specific for TTP (George, 2009). Decreased
activity < 10% is suggestive but not specific for TTP. Gene mutations versus autoantibodies are still a consideration. Finally, both HUS and TTP can be triggered by autoimmune disease, so evaluation of antinuclear antibody, lupus anticoagulant, and antiphospholipid antibody are also important (Ariceta et al., 2009). Renal biopsy is not needed for diagnosis; however, it is sometimes undertaken, especially in severe renal failure or patients with recurrent disease. Disctinctive findings on biopsy may help differentiate HUS from TTP (Banerjee, 2009).
1120
K. WEBSTER AND E. SCHNITZLER
TREATMENT The mainstay of treatment for typical HUS is supportive care. Volume resuscitation, fluid and electrolyte monitoring, and transfusion of blood products are common, as is temporary need for dialysis (Lowe and Werner, 2005; Scheiring et al., 2008; Pomajzl et al., 2009). Treatment of neurologic manifestations is most often associated with control of seizure activity, with care to address any electrolyte imbalance as a potential cause.
Antibiotics Antibiotic therapy is necessary in infections due to Shigella or S. pneumoniae. In other causes of diarrheal HUS, there have been reports of worsened outcomes with antibiotic treatment. A meta-analysis of studies in which antibiotics were used was unable to demonstrate conclusively that harm occurs, although wide variation in treatments was observed (Safdar et al., 2002; Banerjee, 2009; Mohsin et al., 2010).
Cobalamin replacement In cases of cobalamin deficiency, supplementation may help to prevent future episodes (Banerjee, 2009). Unfortunately, despite therapy this disorder is often associated with progression of severe neurologic deficits due to the underlying homocysteine accumulation (Martinielli et al., 2011).
Plasma infusion and plasmapheresis Plasma infusion has been reported to be of benefit in some patients with atypical HUS or TTP. The goal of plasma infusion is to replace complement factors or ADAMTS13 enzyme that are deficient in the afflicted patient. In patients who have deficiencies, marked improvement is reported (Banerjee, 2009). Since many of these deficiencies may be caused not only by decreased production but by destruction via autoantibodies, plasma infusion alone may in some cases be harmful. HUS caused by pneumococcal infection (Banerjee, 2009) and by complement antibodies (Boyer et al., 2010) have both been worsened by plasma infusion. Because the underlying etiology is often unknown at the time of presentation, initial empiric therapy should be plasma exchange to remove the offending antibody. Plasma infusion may be useful in preventing recurrence, once the underlying deficiency has been identified (Kohli and Gulati, 2006; Loirat et al., 2010).
Immunotherapy Plasma exchange is likely to be effective in only 30–50% of patients with atypical HUS (Ariceta et al., 2009; Banerjee, 2009). Some patients may show an initial
response but this response is not sustained and/or repeated lifelong prophylactic treatment is needed. In such patients, reports of treatment with corticosteroids, vincristine, azathioprine, and cyclophosphamide have reported anecdotal success (Michael et al., 2009; Boyer et al., 2010). Often a combination of both immunosuppression and intermittent plasma exchange is necessary to sustain remission in severe relapsing forms of the disease. Inhibition of complement may be effective in aHUS due to complement protein deficiencies. Eculizumab and rituximab have been reported as effective therapies in both atypical HUS (Banerjee, 2009; Mache et al., 2009; Boyer et al., 2010; K€ose et al., 2010) and chronic relapsing TTP (Levandovsky et al., 2008). Currently, investigations are ongoing involving urtoxazumab, a targeted antibody therapy to neutralize Shiga toxin (Lopez et al., 2010). While this may help prevent the cascade of events leading to full HUS, the challenge will be providing therapy within 24–72 hours of exposure (Bitzan et al., 2010). Further investigation of this therapy is needed to provide more conclusive evidence of effect.
Transplantation Patients with aHUS may progress to renal failure and ultimately require transplantation. Unfortunately, as aHUS is most commonly associated with defective or deficient complement protein, the risk of disease recurrence or graft rejection is high (Cheong, 2009).
Complement therapy In variations of HUS associated with deficiency of complement regulatory proteins, replacement of these factors would be beneficial and more specific than plasma infusion alone. While no specific factor is currently available, work is ongoing to develop recombinant or concentrate of these important complement factors (Johnson and Taylor, 2008). Overall, the vast array of etiology and pathophysiology that underlies HUS creates a clinical challenge, with careful attention to presentation, family history, and diagnosis in order to achieve the proper diagnosis and therapy.
REFERENCES Ariceta G, Besbas N, Johnson S et al. (2009). Guideline for the investigation and initial therapy of diarrhea-negative hemolytic uremic syndrome. Pediatr Nephrol 24: 687–696. Bale JF Jr, Brasher C, Siegler RL (1980). CNS manifestations of the hemolytic-uremic syndrome. Relationship to
HEMOLYTIC UREMIC SYNDROME metabolic alterations and prognosis. Am J Dis Child 134: 869–872. Banerjee S (2009). Hemolytic uremic syndrome. Indian Pediatr 46: 1075–1084. Barit G, Sakarcan A (2005). Antibiotic resistant Streptococcus pneumoniae and hemolytic uremic syndrome. Eur J Pediatr 164: 414–416. Barnett ND, Kaplan AM, Bernes SM et al. (1995). Hemolytic uremic syndrome with particular involvement of basal ganglia and favorable outcome. Pediatr Neurol 12: 155–158. Bell BP, Griffin PM, Lozano P et al. (1997). Predictors of hemolytic uremic syndrome in children during a large outbreak of Escherichia coli O157:H7 infections. Pediatrics 100: E12. Besbas N, Karpman D, Landau D et al. (2006). A classification of hemolytic uremic syndrome and thrombotic thrombocytopenic purpura and related disorders. Kidney Int 70: 423–431. Bitzan M, Schaefer F, Reymond D (2010). Treatment of typical (enteropathic) hgemolytic uremic syndrome. Semin Thromb Hemost 36: 594–610. Bouts AH, Roofthooft MTR, Salomous GS et al. (2010). CD46-associated atypical hemolytic uremic syndrome with uncommon course caused by cblC deficiency. Pediatr Nephrol 25: 2547–2548. Boyer O, Balzamo E, Charbit M et al. (2010). Pulse cyclophosphamide therapy and clinical remission in atypical hemolytic uremic syndrome with anti-complement factor H autoantibodies. Am J Kidney Dis 55: 923–927. Brandt J, Wong C, Mihm S et al. (2002). Invasive pneumococcal disease and hemolytic uremic syndrome. Pediatrics 110: 371–376. ¨ et al. (2011). Hemolytic ureC¸altik A, Aky€ uz SG, Erdogan O mic syndrome triggered with a new pandemic virus: influenza A (H1N1). Pediatr Nephrol 26: 147–148. Centers for Disease Control and Prevention (2009). Morbidity and Mortality Weekly Report: Recommendations for diagnosis of Shiga toxin-producing Escherichia coli infections by clinical laboratories. October 16, 2009, Vol. 58, No. RR-12, pp. 1–14. Cerda J, Lameire N, Eggers P et al. (2008). Epidemiology of acute kidney injury. Clin J Am Soc Nephrol 3: 881–886. Chaturvedi S, Licht C, Langlois V (2010). Hemolytic uremic syndrome caused by Bordetella pertussis infection. Pediatr Nephrol 25: 1351–1364. Cheong H (2009). Can liver-kidney transplantation cure aHUS? Nephrology 5: 556–557. Cimolai N, Morrison BJ, Carter JE (1992). Risk factors for the central nervous system manifestations of gastroenteritisassociated hemolytic-uremic syndrome. Pediatrics 90: 616–621. Desch K, Motto D (2007). Is there a shared pathophysiology for thrombotic thrombocytopenic purpura and hemolyticuremic syndrome? J Am Soc Nephrol 18: 2457–2460. Dhuna A, Pascual-Leone A, Talwar D et al. (1992). EEG and seizures in children with hemolytic-uremic syndrome. Epilepsia 33: 482–486. DiMario FJ Jr, Br€onte-Stewart H, Sherbotie J et al. (1987). Lacunar infarction of the basal ganglia as a complication
1121
of hemolytic-uremic syndrome: MRI and clinical correlations. Clin Pediatr 25: 586. Eriksson KJ, Boyd SG, Tasker RC (2001). Acute neurology and neurophysiology of haemolytic-uraemic syndrome. Arch Dis Child 84: 434–435. Gasser C, Gautier E, Steck A et al. (1955). Hemolytic-uremic syndrome: bilateral necrosis of the renal cortex in acute acquired hemolytic anemia. Schweiz Med Wochenschr 85: 905–909. George JN (2009). The thrombotic thrombocytopenic purpura and hemolytic uremic syndromes: overview of pathogenesis (experience of the Oklahoma TTP-HUS Registry, 1989–2007). Kidney Int 75 (Suppl 112): S8–S10. Glatstein M, Miller E, Garcia-Boumissen F et al. (2010). Timing and utility of ultrasound in diarrhea-associated hemolytic uremic syndrome: 7-year experience of a large tertiary care hospital. Clin Pediatr 49: 318. Gould LH, Demma L, Jones TF et al. (2009). Hemolytic uremic syndrome and death in persons with Escherichia coli O157:H7 infection, Foodborne Diseases Active Surveillance Network Sites, 2000–2006. Clin Infect Dis 49: 1480–1485. Hahn JS, Havens PL, Higgins JJ et al. (1989). Neurological complications of hemolytic-uremic syndrome. J Child Neurol 4: 108–113. Hinchey J, Chaves C, Appigani B et al. (1996). A reversible posterior leukoencephalopathy syndrome. N Engl J Med 334: 494. Johnson S, Taylor CM (2008). What’s new in haemolytic uraemic syndrome? Eur J Pediatr 167: 965–971. Johnson S, Taylor CM (2009). In: ED Ainer, D Ellis (Eds.), Pediatric Nephrology. 6th edn. Springer, pp. 1155–1180. Karpman D, Sartz L, Johnson S (2010). Pathophysiology of typical hemolytic uremic syndrome. Semin Thromb Hemost 36: 575–585. Kavanagh D, Richards A, Fremeaux-Bacchi V et al. (2007). Screening for complement system abnormalities in patients with atypical hemolytic uremic syndrome. Clin J Am Soc Nephrol 2: 591–596. Kohli R, Gulati S (2006). Plasma infusion therapy in atypical hemolytic uremic syndrome – long term outcome. Indian Pediatr 43: 164–166. ¨ , Zimmerhackl L-B, Jungraithmayr T et al. (2010). New K€ ose O treatment options for atypical hemolytic uremic syndrome with the complement inhibitor eculizumab. Semin Thromb Hemost 36: 669–672. Lei T-H, Hsia S-H, Wu C-T et al. (2010). Streptococcus pneumoniae-associated haemolytic uremic syndrome following influenza A virus infection. Eur J Pediatr 169: 237–239. Levandosky M, Harvey D, Lara P et al. (2008). Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS): a 24-year clinical experience with 178 patients. J Hematol Oncol 1: 23 http://www.jhoonline.org/ content/1/1/23. Loirat C, Noris M, Fremeaux-Bacchi V (2008). Complement and the atypical hemolytic uremic syndrome in children. Pediatr Nephrol 123: 1957–1972.
1122
K. WEBSTER AND E. SCHNITZLER
Loirat C, Garnier A, Sellier-Leclerc A-L et al. (2010). Plasmatherapy in atypical hemolytic uremic syndrome. Semin Thromb Hemost 36: 673–681. Lopez EL, Contrini MM, Glatstein E et al. (2010). Safety and pharmacokinetics of urtoxazumab, a humanized monoclonal antibody, against Shiga-like toxin 2 in healthy adults and in pediatric patients infected with Shiga-like toxin-producing Escherichia coli. Antimicrob Agents Chemother 54: 239–243. Lowe EJ, Werner EJ (2005). Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome in children and adolescents. Semin Thromb Hemost 31: 717–729. Mache CJ, Acham-Roschitz B, Fremeaux-Bacchi V et al. (2009). Complement inhibitor eculizumab in atypical hemolytic uremic syndrome. Clin J Am Soc Nephrol 4: 1312–1316. Martinelli D, Deodato F, Dionisi-Vici C (2011). Cobalamin C defect: natural history, pathophysiology, and treatment. J Inherit Metab Dis 34: 127–135. Melmann A, Fruth A, Friedrich AW et al. (2009). Phylogeny and disease association of Shiga toxin-producing Escherichi coli O91. Emerg Infect Dis 15: 1474–1477. Michael M, Elliott EJ, Craig JC et al. (2009). Interventions for hemolytic uremic syndrome and thrombotic thrombocytopenic purpura: a systematic review of randomized controlled trials. Am J Kidney Dis 53: 259–272. Moake JL (2002). Thrombotic microangiopathies. N Engl J Med 347: 589–600. Mohsin M, Haque A, Ali A et al. (2010). Effects of ampicillin, gentamicin, and cefotaxime on the release of Shiga toxins from Shiga toxin-producing Escherichia coli isolated during a diarrhea episode in Faisalabad, Pakistan. Foodborne Pathog Dis 7: 85–90. Nakahata T, Tanaka H, Tateyama T et al. (2001). Thrombotic stroke in a child with diarrhea-associated hemolytic-uremic syndrome with a good recovery. Tohoku J Exp Med 193: 73–77. Nolasco LH, Turner NA, Bernardo A et al. (2005). Hemolytic uremic syndrome-associated Shiga toxins promote endothelial-cell secretion and impair ADAMTS13 cleavage of unusually large von Willebrand factor multimers. Blood 106: 4199–4209. Ogura H, Takaoka M, Kishi M et al. (1998). Reversible MR findings of hemolytic uremic syndrome with mild encephalopathy. AJNR Am J Neuroradiol 19: 1144–1145. Pomajzl RJ, Varman M, Holst A et al. (2009). Hemolytic uremic syndrome (HUS) – incidence and etiologies at a regional Children’s Hospital in 2001–2006. Eur J Clin Microbiol Infect Dis 28: 1431–1435. Printza N, Roilides E, Kotsiou M et al. (2011). Pandemic influenza A (H1N1) 2009-associated hemolytic uremic syndrome. Pediatr Nephrol 26: 143–144. Qamar IU, Ohali M, MacGregor DL et al. (1996). Long-term neurological sequelae of hemolytic-uremic syndrome: a preliminary report. Pediatr Nephrol 10: 504–506.
Quintrec ML, Roumenina L, Noris M et al. (2010). Atypical hemolytic uremic syndrome associated with mutations in complement regulator genes. Semin Thromb Hemost 36: 641–652. Razzaq S (2006). Hemolytic uremic syndrome: an emerging health risk. Am Fam Physician 74: 991–996. Rivero MA, Passucci JA, Rodriguez EM et al. (2010). Role and clinical course of verotoxigenic Escherichia coli infections in childhood acute diarrhoea in Argentina. J Med Microbiol 59: 345–352. Rooney JC, Anderson RM, Hopkins IJ (1971). Clinical and pathologic aspects of central nervous system involvement in the haemolytic uraemic syndrome. Proc Aust Assoc Neurol 8: 67–75. Ruggenenti P, Noris M, Remuzzi G (2001). Thrombotic microangiopathy, hemolytic uremic syndrome, and thrombotic thrombocytopenic purpura. Kidney Int 60: 831–846. Rust R, Chun R (1999). Interrelationships between renal and neurologic diseases and therapies. In: KF Swaiman, S Ashwal (Eds.), Pediatric Neurology Principles and Practice. 3rd edn. Mosby, St Louis, pp. 1403–1437. Rust RS, Worrel TE (2009). Hemolytic uremic syndrome. eMedicine Neurology 1–30. Safdar N, Said A, Gangon RE et al. (2002). Risk of hemolytic uremic syndrome after antibiotic treatment of Escherichia coli O157:H7 enteritis: a meta-analysis. JAMA 288: 996–1001. Scheiring J, Andreoli SP, Zimmerhackl LB (2008). Treatment and outcome of Shiga-toxin-associated hemolytic uremic syndrome. Pediatr Nephrol 23: 1749–1760. Scheiring J, Rosales A, Zimmerhackl LB (2010). Today’s understanding of the haemolytic uraemic syndrome. Eur J Pediatr 169: 7–13. Schlieper A, Orrbine E, Wells GA et al. (1999). Neuropsychological sequelae of haemolytic uraemic syndrome. Arch Dis Child 80: 214–220. Schneppenheim R, Budde U, Hassenpflug W et al. (2004). Severe ADAMTS-13 deficiency in childhood. Semin Hematol 41: 83–89. Sebire G, Husson B, Lasser C et al. (1995). Encephalopathy induced by arterial hypertension: clinical, radiological and therapeutic aspects. Arch Pediatr 2: 513. Sharma J, Bharadawa K, Shah K et al. (1993). Plasmodium vivax malaria presenting as hemolytic-uremic syndrome. Indian Pediatr 30: 369–371. Sharma AP, Greenberg CR, Prasad AN et al. (2007). Hemolytic uremic syndrome secondary to cobalamin C C (Cb1c) disorder. Pediatr Nephrol 22: 2097–2103. Sheth KJ, Swick HM, Haworth N (1986). Neurological involvement in hemolytic-uremic syndrome. Ann Neurol 19: 90–93. Steinberg A, Ish-Horowitcz M, el-Peleg O et al. (1986). Stroke in a patient with hemolytic-uremic syndrome with a good outcome. Brain Dev 8: 70–72.
HEMOLYTIC UREMIC SYNDROME Steinborn M, Leiz S, R€ udisser K et al. (2004). CT and MRI in haemolytic uraemic syndrome with central nervous system involvement: distribution of lesions and prognostic value of imaging findings. Pediatr Radiol 34: 805–810. Stewart CL, Tina LU (1993). Hemolytic uremic syndrome. Pediatr Rev 14: 218–224.
1123
Toldo I, Manara R, Cogo P et al. (2009). Diffusion-weighted imaging findings in hemolytic uremic syndrome with central nervous system involvement. J Child Neurol 24: 247–250. Upadhyahya K, Barwick K, Fishaut M et al. (1980). The importance of non-renal involvement in hemolytic uremic syndrome. Pediatrics 65: 115–120.
